For the work on quercetin and mitochondria, a next step could be to analyse the effects in the muscle model to see if they are consistent or cell/tissue-specific. Mitochondrial assays were already tested on the LHCN-M2 myotubes and so this would be straightforward to set up. Furthermore, the metabolites for which effects on glucose metabolism were seen in the muscle could be tested for their potential roles in mitochondrial function too. The effects of quercetin were dose-dependent, with effects on complex I activity and ROS levels seen with 2.5 µM; any lower and the effects would likely not have been detected. To investigate effects even closer to the typical physiological range, a model could be established to try growing the HepG2 cells for a longer period (and/or through multiple passages) and treating with quercetin long-term i.e. daily treatments with 1 µM or even 0.1 µM, to see if changes are detectable in these assays, with comparisons to the 24 h treatments with 10 µM. Further investigations into the effects of quercetin on metabolic flux could be investigated using ion chromatography; analyses of lactate, pyruvate, succinate, citrate and so on would be interesting in the current HepG2 system and one would hypothesise seeing quercetin driving flux away from the glycolytic-dependent ATP synthesis towards the TCA cycle and mitochondrial respiration. Extracellular metabolites were measured by high- performance liquid chromatography recently (Niklas, Nonnenmacher et al. 2012) and this could be taken further by measuring intracellular metabolites in cell lysate extracts as well as the extracellular in the media, and comparing normal and high glucose. Furthermore, the effects on mitochondria will affect lipid metabolism as well as glucose, so analysis of the lipidome in HepG2 grown in normal and high glucose and treated with quercetin would be an interesting additional study; quercetin was already shown to exert lipid-lowering effects in the livers of diabetic mice via increased mitochondrial function (Kim, Kwon et al. 2015).
It would be challenging to investigate the effects of quercetin on hepatic mitochondria in
vivo for obvious reasons; mitochondria could be isolated from rodent livers following
quercetin intervention for example, but this certainly wouldn’t be possible in humans. An in vitro setup could involve obtaining primary hepatocytes from normal and diabetic patients and treating these with quercetin to see how the effects compare, but this heavily relies on tissue availability and a large cohort to see beyond inter-individual variability. An easier ex vivo approach may be to take muscle biopsies following a long-term quercetin intervention and analyse the samples on the high-resolution respirometer and/or isolate mitochondria from the tissue.
The obvious studies to be carried out next for the effects of (poly)phenol metabolites on glucose uptake and metabolism are human interventions. With an in vitro mechanism of action established for IVAS, this would be a promising compound to start with. An intervention with the berry purée used in the studies by Pimpão et al. (Pimpao, Dew et al. 2014, Pimpao, Ventura et al. 2015), from which the phenolic sulfate profile in this study was selected, may lower glycaemia in participants, though it would be unclear if this was an effect on muscle uptake or more so on the inhibition of carbohydrate digestion and absorption seen with berries in previous interventions (Nyambe-Silavwe and Williamson 2016). Intervention with a cyanidin 3-O-glucoside tablet, such as that used in pharmacokinetic studies (Czank, Cassidy et al. 2013, de Ferrars, Czank et al. 2014), instead of berries may result in more specific metabolites at least, or encapsulating IVAS so a controlled dose reaches the bloodstream.
Finally, to expand on the beneficial roles of (poly)phenol metabolites, and to make the
in vitro models closer to the in vivo situation, the HepG2 and/or LHCN-M2 cells could
be transfected with OAT-expressing plasmids to upregulate the transporters associated with the facilitated uptake of the sulfated conjugates (Wong, Akiyama et al. 2012). In the muscle study here the sulfated conjugates were not taken up and their effects may differ if they were. It would also be interesting to compare the effects of quercetin aglycone and quercetin 3′-O-sulfate on the mitochondrial function and cellular metabolism in HepG2 cells. Likewise, LHCN-M2 transfected with GLUT4 to increase expression beyond the low endogenous level would further confirm the GLUT4 translocation- stimulated mechanism of IVAS and other metabolites.
References
ENCODE (2012). "An integrated encyclopedia of DNA elements in the human genome." Nature 489(7414): 57-74.
Adisakwattana, S., N. Ngamrojanavanich, K. Kalampakorn, W. Tiravanit, S. Roengsumran and S. Yibchok-Anun (2004). "Inhibitory activity of cyanidin-3- rutinoside on alpha-glucosidase." J Enzyme Inhib Med Chem 19(4): 313-316.
Aggarwal, B. B., A. Bhardwaj, R. S. Aggarwal, N. P. Seeram, S. Shishodia and Y. Takada (2004). "Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies." Anticancer Res 24(5a): 2783-2840.
Aggeli, I. K., D. Theofilatos, I. Beis and C. Gaitanaki (2011). "Insulin-induced oxidative stress up-regulates heme oxygenase-1 via diverse signaling cascades in the C2 skeletal myoblast cell line." Endocrinology 152(4): 1274-1283.
Agronomique., I. N. d. l. R. (2014). "PhytoHub version 1.0: a food metabolome database dedicated to dietary phytochemicals." from www.phytohub.eu.
Ahn, J., H. Lee, S. Kim, J. Park and T. Ha (2008). "The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways." Biochem Biophys Res Commun 373(4): 545-549.
Aires, V., E. Limagne, A. K. Cotte, N. Latruffe, F. Ghiringhelli and D. Delmas (2013). "Resveratrol metabolites inhibit human metastatic colon cancer cells progression and synergize with chemotherapeutic drugs to induce cell death." Mol Nutr Food Res
57(7): 1170-1181.
Akash, M. S., K. Rehman and S. Chen (2014). "Spice plant Allium cepa: dietary supplement for treatment of type 2 diabetes mellitus." Nutrition 30(10): 1128-1137. Akkarachiyasit, S., P. Charoenlertkul, S. Yibchok-Anun and S. Adisakwattana (2010).
"Inhibitory activities of cyanidin and its glycosides and synergistic effect with acarbose against intestinal alpha-glucosidase and pancreatic alpha-amylase." Int J Mol Sci 11(9): 3387-3396.
Al-Khalili, L., A. V. Chibalin, K. Kannisto, B. B. Zhang, J. Permert, G. D. Holman, E. Ehrenborg, V. D. Ding, J. R. Zierath and A. Krook (2003). "Insulin action in cultured human skeletal muscle cells during differentiation: assessment of cell surface GLUT4 and GLUT1 content." Cell Mol Life Sci 60(5): 991-998.
Aliciguzel, Y., I. Ozen, M. Aslan and U. Karayalcin (2003). "Activities of xanthine oxidoreductase and antioxidant enzymes in different tissues of diabetic rats." J Lab Clin Med 142(3): 172-177.
Alkhalidy, H., W. Moore, Y. Zhang, R. McMillan, A. Wang, M. Ali, K.-S. Suh, W. Zhen, Z. Cheng, Z. Jia, M. Hulver and D. Liu (2015). "Small Molecule Kaempferol Promotes Insulin Sensitivity and Preserved Pancreatic β-Cell Mass in Middle- Aged Obese Diabetic Mice." Journal of Diabetes Research 2015: 14.
Alvim, R. O., M. R. Cheuhen, S. R. Machado, A. G. Sousa and P. C. Santos (2015). "General aspects of muscle glucose uptake." An Acad Bras Cienc 87(1): 351-368. Amiot, M. J., C. Riva and A. Vinet (2016). "Effects of dietary polyphenols on metabolic
syndrome features in humans: a systematic review." Obes Rev 17(7): 573-586. Andersen, G., P. Koehler and V. Somoza (2008). "POSTPRANDIAL GLUCOSE AND
FREE FATTY ACID RESPONSE IS IMPROVED BY WHEAT BREAD FORTIFIED WITH GERMINATED WHEAT SEEDLINGS." Current Topics in Nutraceutical Research 6(1): 15-21.
Andrzejewski, S., S. P. Gravel, M. Pollak and J. St-Pierre (2014). "Metformin directly acts on mitochondria to alter cellular bioenergetics." Cancer Metab 2: 12.
Anhê, G. F., M. M. Okamoto, A. Kinote, C. Sollon, C. Lellis-Santos, F. F. Anhê, G. A. Lima, S. M. Hirabara, L. A. Velloso, S. Bordin and U. F. Machado (2012). "Quercetin decreases inflammatory response and increases insulin action in skeletal muscle of ob/ob mice and in L6 myotubes." European Journal of Pharmacology 689(1): 285- 293.
Arab, L., W. Liu and D. Elashoff (2009). "Green and black tea consumption and risk of stroke: a meta-analysis." Stroke 40(5): 1786-1792.
Ardiansyah, Y. Ohsaki, H. Shirakawa, T. Koseki and M. Komai (2008). "Novel effects of a single administration of ferulic acid on the regulation of blood pressure and the hepatic lipid metabolic profile in stroke-prone spontaneously hypertensive rats." J Agric Food Chem 56(8): 2825-2830.
Arner, E. S. and A. Holmgren (2000). "Physiological functions of thioredoxin and thioredoxin reductase." Eur J Biochem 267(20): 6102-6109.
Arts, I. C. (2008). "A review of the epidemiological evidence on tea, flavonoids, and lung cancer." J Nutr 138(8): 1561S-1566S.
Aung, T. N., Z. Qu, R. D. Kortschak and D. L. Adelson (2017). "Understanding the Effectiveness of Natural Compound Mixtures in Cancer through Their Molecular Mode of Action." Int J Mol Sci 18(3).
Austin, S. and J. St-Pierre (2012). "PGC1alpha and mitochondrial metabolism--emerging concepts and relevance in ageing and neurodegenerative disorders." J Cell Sci 125(Pt 21): 4963-4971.
Babu, P. V., D. Liu and E. R. Gilbert (2013). "Recent advances in understanding the anti- diabetic actions of dietary flavonoids." J Nutr Biochem 24(11): 1777-1789.
Baeza, G., E. M. Bachmair, S. Wood, R. Mateos, L. Bravo and B. de Roos (2017). "The colonic metabolites dihydrocaffeic acid and dihydroferulic acid are more effective inhibitors of in vitro platelet activation than their phenolic precursors." Food Funct
8(3): 1333-1342.
Bahadoran, Z., P. Mirmiran and F. Azizi (2013). "Dietary polyphenols as potential nutraceuticals in management of diabetes: a review." J Diabetes Metab Disord 12(1): 43.
Baldelli, S., K. Aquilano and M. R. Ciriolo (2014). "PGC-1alpha buffers ROS-mediated removal of mitochondria during myogenesis." Cell Death Dis 5: e1515.
Bali, E. B., V. Ergin, L. Rackova, O. Bayraktar, N. Kucukboyaci and C. Karasu (2014). "Olive leaf extracts protect cardiomyocytes against 4-hydroxynonenal-induced toxicity in vitro: comparison with oleuropein, hydroxytyrosol, and quercetin." Planta Med 80(12): 984-992.
Banh, R. S., C. Iorio, R. Marcotte, Y. Xu, D. Cojocari, A. A. Rahman, J. Pawling, W. Zhang, A. Sinha, C. M. Rose, M. Isasa, S. Zhang, R. Wu, C. Virtanen, T. Hitomi, T. Habu, S. S. Sidhu, A. Koizumi, S. E. Wilkins, T. Kislinger, S. P. Gygi, C. J. Schofield, J. W. Dennis, B. G. Wouters and B. G. Neel (2016). "PTP1B controls non- mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia." Nat Cell Biol 18(7): 803-813.
Bantle, J. P. (2009). "Dietary Fructose and Metabolic Syndrome and Diabetes." The Journal of Nutrition 139(6): 1263S-1268S.
Barazzoni, R., M. Zanetti, G. Gortan Cappellari, A. Semolic, M. Boschelle, E. Codarin, A. Pirulli, L. Cattin and G. Guarnieri (2012). "Fatty acids acutely enhance insulin- induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-kappaB inhibitor
(IkappaB)-nuclear factor-kappaB (NFkappaB) activation in rat muscle, in the absence of mitochondrial dysfunction." Diabetologia 55(3): 773-782.
Bareja, A., J. A. Holt, G. Luo, C. Chang, J. Lin, A. C. Hinken, J. M. Freudenberg, W. E. Kraus, W. J. Evans and A. N. Billin (2014). "Human and mouse skeletal muscle stem cells: convergent and divergent mechanisms of myogenesis." PLoS One 9(2): e90398. Barnes, S. (2008). "Nutritional Genomics, Polyphenols, Diets, and Their Impact on
Dietetics." Journal of the American Dietetic Association 108(11): 1888-1895.
Ben Salem, I., M. Boussabbeh, I. Graiet, A. Rhouma, H. Bacha and S. Abid Essefi (2016). "Quercetin protects HCT116 cells from Dichlorvos-induced oxidative stress and apoptosis." Cell Stress and Chaperones 21(1): 179-186.
Berg, J. M., J. L. Tymoczko and L. Stryer (2002). Biochemistry, Fifth Edition, W.H. Freeman.
Bhatt, J. K., S. Thomas and M. J. Nanjan (2012). "Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus." Nutr Res 32(7): 537-541.
Bhattacharya, S., K. B. Christensen, L. C. Olsen, L. P. Christensen, K. Grevsen, N. J. Faergeman, K. Kristiansen, J. F. Young and N. Oksbjerg (2013). "Bioactive components from flowers of Sambucus nigra L. increase glucose uptake in primary porcine myotube cultures and reduce fat accumulation in Caenorhabditis elegans." J Agric Food Chem 61(46): 11033-11040.
Birben, E., U. M. Sahiner, C. Sackesen, S. Erzurum and O. Kalayci (2012). "Oxidative stress and antioxidant defense." World Allergy Organ J 5(1): 9-19.
Blake, R. and I. A. Trounce (2014). "Mitochondrial dysfunction and complications associated with diabetes." Biochim Biophys Acta 1840(4): 1404-1412.
Bloemberg, D. and J. Quadrilatero (2012). "Rapid Determination of Myosin Heavy Chain Expression in Rat, Mouse, and Human Skeletal Muscle Using Multicolor Immunofluorescence Analysis." PLoS ONE 7(4): e35273.
Bohn, T., G. J. McDougall, A. Alegria, M. Alminger, E. Arrigoni, A. M. Aura, C. Brito, A. Cilla, S. N. El, S. Karakaya, M. C. Martinez-Cuesta and C. N. Santos (2015). "Mind the gap-deficits in our knowledge of aspects impacting the bioavailability of phytochemicals and their metabolites--a position paper focusing on carotenoids and polyphenols." Mol Nutr Food Res 59(7): 1307-1323.
Boocock, D. J., G. E. Faust, K. R. Patel, A. M. Schinas, V. A. Brown, M. P. Ducharme, T. D. Booth, J. A. Crowell, M. Perloff, A. J. Gescher, W. P. Steward and D. E. Brenner (2007). "Phase I dose escalation pharmacokinetic study in healthy volunteers of
resveratrol, a potential cancer chemopreventive agent." Cancer Epidemiol Biomarkers Prev 16(6): 1246-1252.
Boots, A. W., H. Li, R. P. Schins, R. Duffin, J. W. Heemskerk, A. Bast and G. R. Haenen (2007). "The quercetin paradox." Toxicol Appl Pharmacol 222(1): 89-96.
Borges, G., W. Mullen, A. Mullan, M. E. Lean, S. A. Roberts and A. Crozier (2010). "Bioavailability of multiple components following acute ingestion of a polyphenol- rich juice drink." Mol Nutr Food Res 54 Suppl 2: S268-277.
Boucher, J., A. Kleinridders and C. R. Kahn (2014). "Insulin Receptor Signaling in Normal and Insulin-Resistant States." Cold Spring Harbor Perspectives in Biology
6(1): a009191.
Boue, S. M., K. W. Daigle, M. H. Chen, H. Cao and M. L. Heiman (2016). "Antidiabetic Potential of Purple and Red Rice (Oryza sativa L.) Bran Extracts." J Agric Food Chem
64(26): 5345-5353.
Boushel, R., E. Gnaiger, P. Schjerling, M. Skovbro, R. Kraunsoe and F. Dela (2007). "Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle." Diabetologia 50(4): 790-796.
Bozzetto, L., G. Annuzzi, G. Pacini, G. Costabile, C. Vetrani, M. Vitale, E. Griffo, A. Giacco, C. De Natale, S. Cocozza, G. Della Pepa, A. Tura, G. Riccardi and A. A. Rivellese (2015). "Polyphenol-rich diets improve glucose metabolism in people at high cardiometabolic risk: a controlled randomised intervention trial." Diabetologia
58(7): 1551-1560.
Bradford, M. M. (1976). "A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding." Anal Biochem 72: 248-254.
Brand, M. D. (2010). "The sites and topology of mitochondrial superoxide production." Exp Gerontol 45(7-8): 466-472.
Brand, M. D. and D. G. Nicholls (2011). "Assessing mitochondrial dysfunction in cells." Biochem J 435(2): 297-312.
Brandt, U. (2006). "Energy converting NADH:quinone oxidoreductase (complex I)." Annu Rev Biochem 75: 69-92.
Brasnyo, P., G. A. Molnar, M. Mohas, L. Marko, B. Laczy, J. Cseh, E. Mikolas, I. A. Szijarto, A. Merei, R. Halmai, L. G. Meszaros, B. Sumegi and I. Wittmann (2011). "Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients." Br J Nutr 106(3): 383-389.
Bravo, L. (1998). "Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance." Nutr Rev 56(11): 317-333.
Breen, D. M., T. Sanli, A. Giacca and E. Tsiani (2008). "Stimulation of muscle cell glucose uptake by resveratrol through sirtuins and AMPK." Biochem Biophys Res Commun 374(1): 117-122.
Breschi, A., T. R. Gingeras and R. Guigo (2017). "Comparative transcriptomics in human and mouse." Nat Rev Genet 18(7): 425-440.
Brown, V. A., K. R. Patel, M. Viskaduraki, J. A. Crowell, M. Perloff, T. D. Booth, G. Vasilinin, A. Sen, A. M. Schinas, G. Piccirilli, K. Brown, W. P. Steward, A. J. Gescher and D. E. Brenner (2010). "Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin- like growth factor axis." Cancer Res 70(22): 9003-9011.
Brownlee, M. (2001). "Biochemistry and molecular cell biology of diabetic complications." Nature 414(6865): 813-820.
Bruce, C. R., S. Risis, J. R. Babb, C. Yang, G. M. Kowalski, A. Selathurai, R. S. Lee- Young, J. M. Weir, K. Yoshioka, Y. Takuwa, P. J. Meikle, S. M. Pitson and M. A. Febbraio (2012). "Overexpression of sphingosine kinase 1 prevents ceramide accumulation and ameliorates muscle insulin resistance in high-fat diet-fed mice." Diabetes 61(12): 3148-3155.
Burkon, A. and V. Somoza (2008). "Quantification of free and protein-bound trans- resveratrol metabolites and identification of trans-resveratrol-C/O-conjugated diglucuronides - two novel resveratrol metabolites in human plasma." Mol Nutr Food Res 52(5): 549-557.
Buss, G. D., J. Constantin, L. C. de Lima, G. R. Teodoro, J. F. Comar, E. L. Ishii- Iwamoto and A. Bracht (2005). "The action of quercetin on the mitochondrial NADH to NAD(+) ratio in the isolated perfused rat liver." Planta Med 71(12): 1118-1122. Butler, A. E., J. Janson, S. Bonner-Weir, R. Ritzel, R. A. Rizza and P. C. Butler (2003).
"Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes." Diabetes 52(1): 102-110.
Canto, C., Z. Gerhart-Hines, J. N. Feige, M. Lagouge, L. Noriega, J. C. Milne, P. J. Elliott, P. Puigserver and J. Auwerx (2009). "AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity." Nature 458(7241): 1056-1060.
Cao, H., J. F. Urban, Jr. and R. A. Anderson (2008). "Cinnamon polyphenol extract affects immune responses by regulating anti- and proinflammatory and glucose transporter gene expression in mouse macrophages." J Nutr 138(5): 833-840.
Cardona, F., C. Andres-Lacueva, S. Tulipani, F. J. Tinahones and M. I. Queipo-Ortuno (2013). "Benefits of polyphenols on gut microbiota and implications in human health." J Nutr Biochem 24(8): 1415-1422.
Carling, D. (2017). "AMPK signalling in health and disease." Curr Opin Cell Biol 45: 31-37.
Carrasco-Pozo, C., M. L. Mizgier, H. Speisky and M. Gotteland (2012). "Differential protective effects of quercetin, resveratrol, rutin and epigallocatechin gallate against mitochondrial dysfunction induced by indomethacin in Caco-2 cells." Chem Biol Interact 195(3): 199-205.
Carrasco-Pozo, C., E. Pastene, C. Vergara, M. Zapata, C. Sandoval and M. Gotteland (2012). "Stimulation of cytosolic and mitochondrial calcium mobilization by indomethacin in Caco-2 cells: Modulation by the polyphenols quercetin, resveratrol and rutin." Biochimica et Biophysica Acta (BBA) - General Subjects 1820(12): 2052- 2061.
Carrasco-Pozo, C., K. N. Tan, M. Reyes-Farias, N. De La Jara, S. T. Ngo, D. F. Garcia- Diaz, P. Llanos, M. J. Cires and K. Borges (2016). "The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic beta-cells, glycemic control and inflammation: In vitro and in vivo studies." Redox Biol 9: 229-243.
Carvalho-Peixoto, J., M. R. Moura, F. A. Cunha, P. C. Lollo, W. D. Monteiro, L. M. Carvalho and T. Farinatti Pde (2015). "Consumption of acai (Euterpe oleracea Mart.) functional beverage reduces muscle stress and improves effort tolerance in elite athletes: a randomized controlled intervention study." Appl Physiol Nutr Metab 40(7): 725-733.
Castro-Acosta, M. L., G. N. Lenihan-Geels, C. P. Corpe and W. L. Hall (2016). "Berries and anthocyanins: promising functional food ingredients with postprandial glycaemia-lowering effects." Proc Nutr Soc 75(3): 342-355.
Cavalcanti, R., N. Begaye, M. Costa, L. Bharath, J. Symons, T. Jalili, N. Rajasekaran, Z. Jia and P. Babu (2015). "Metabolites of Blueberry Anthocyanins Suppress Lipotoxicity Induced Endothelial Inflammation." The FASEB Journal 29(1 Supplement).
Cazarolli, L. H., P. Folador, M. G. Pizzolatti and F. R. Mena Barreto Silva (2009). "Signaling pathways of kaempferol-3-neohesperidoside in glycogen synthesis in rat soleus muscle." Biochimie 91(7): 843-849.
Cederroth, C. R., M. Vinciguerra, A. Gjinovci, F. Kuhne, M. Klein, M. Cederroth, D. Caille, M. Suter, D. Neumann, R. W. James, D. R. Doerge, T. Wallimann, P. Meda, M. Foti, F. Rohner-Jeanrenaud, J. D. Vassalli and S. Nef (2008). "Dietary phytoestrogens activate AMP-activated protein kinase with improvement in lipid and glucose metabolism." Diabetes 57(5): 1176-1185.
Ceperuelo-Mallafré, V., M. Ejarque, C. Serena, X. Duran, M. Montori-Grau, M. A. Rodríguez, O. Yanes, C. Núñez-Roa, K. Roche, P. Puthanveetil, L. Garrido-Sánchez, E. Saez, F. J. Tinahones, P. M. Garcia-Roves, A. M. Gómez-Foix, A. R. Saltiel, J. Vendrell and S. Fernández-Veledo (2016). "Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans." Molecular Metabolism 5(1): 5-18.
Ceriello, A. and E. Motz (2004). "Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited." Arterioscler Thromb Vasc Biol 24(5): 816-823.
Chakraborty, S., S. Stalin, N. Das, S. Thakur Choudhury, S. Ghosh and S. Swarnakar (2012). "The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat." Biomaterials 33(10): 2991-3001.
Chan, T., G. Galati and P. J. O'Brien (1999). "Oxygen activation during peroxidase catalysed metabolism of flavones or flavanones." Chem Biol Interact 122(1): 15-25. Chao, C. L., Y. C. Hou, P. D. Chao, C. S. Weng and F. M. Ho (2009). "The antioxidant
effects of quercetin metabolites on the prevention of high glucose-induced apoptosis of human umbilical vein endothelial cells." Br J Nutr 101(8): 1165-1170.
Chatterjee, S., K. Khunti and M. J. Davies (2017). "Type 2 diabetes." Lancet 389(10085): 2239-2251.
Chaudhury, A., C. Duvoor, V. S. Reddy Dendi, S. Kraleti, A. Chada, R. Ravilla, A. Marco, N. S. Shekhawat, M. T. Montales, K. Kuriakose, A. Sasapu, A. Beebe, N. Patil, C. K. Musham, G. P. Lohani and W. Mirza (2017). "Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management." Frontiers in Endocrinology 8: 6.
Chellan, N., C. J. Muller, D. de Beer, E. Joubert, B. J. Page and J. Louw (2012). "An in vitro assessment of the effect of Athrixia phylicoides DC. aqueous extract on glucose metabolism." Phytomedicine 19(8-9): 730-736.
Chen, J.-Q., L. M. Wakefield and D. J. Goldstein (2015). "Capillary nano- immunoassays: advancing quantitative proteomics analysis, biomarker assessment, and molecular diagnostics." Journal of Translational Medicine 13: 182.
Chen, W. P., T. C. Chi, L. M. Chuang and M. J. Su (2007). "Resveratrol enhances insulin secretion by blocking K(ATP) and K(V) channels of beta cells." Eur J Pharmacol
568(1-3): 269-277.
Cheng, C. S., Y. El-Abd, K. Bui, Y.-E. Hyun, R. H. Hughes, W. E. Kraus and G. A. Truskey (2014). "Conditions that promote primary human skeletal myoblast culture and muscle differentiation in vitro." American Journal of Physiology - Cell Physiology 306(4): C385-C395.
Cheng, C. W., V. Villani, R. Buono, M. Wei, S. Kumar, O. H. Yilmaz, P. Cohen, J. B. Sneddon, L. Perin and V. D. Longo (2017). "Fasting-Mimicking Diet Promotes Ngn3- Driven beta-Cell Regeneration to Reverse Diabetes." Cell 168(5): 775-788 e712. Cheng, Z., Y. Tseng and M. F. White (2010). "Insulin signaling meets mitochondria in
metabolism." Trends in endocrinology and metabolism: TEM 21(10): 589-598. Chis, I. C., A. Muresan, A. Oros, A. L. Nagy and S. Clichici (2016). "Protective effects
of Quercetin and chronic moderate exercise (training) against oxidative stress in the liver tissue of streptozotocin-induced diabetic rats." Acta Physiol Hung 103(1): 49- 64.
Cho, J. M., S. Y. Chang, D. B. Kim, P. W. Needs, Y. H. Jo and M. J. Kim (2012). "Effects of physiological quercetin metabolites on interleukin-1beta-induced inducible NOS expression." J Nutr Biochem 23(11): 1394-1402.
Chow, J., J. Rahman, J. C. Achermann, M. T. Dattani and S. Rahman (2016). "Mitochondrial disease and endocrine dysfunction." Nat Rev Endocrinol.
Chung, S., H. Yao, S. Caito, J. W. Hwang, G. Arunachalam and I. Rahman (2010). "Regulation of SIRT1 in cellular functions: role of polyphenols." Arch Biochem Biophys 501(1): 79-90.
Cialdella-Kam, L., D. C. Nieman, W. Sha, M. P. Meaney, A. M. Knab and R. A. Shanely (2013). "Dose-response to 3 months of quercetin-containing supplements on metabolite and quercetin conjugate profile in adults." Br J Nutr 109(11): 1923-1933.
Ciaraldi, T. P., L. Abrams, S. Nikoulina, S. Mudaliar and R. R. Henry (1995). "Glucose transport in cultured human skeletal muscle cells. Regulation by insulin and glucose in nondiabetic and non-insulin-dependent diabetes mellitus subjects." Journal of Clinical Investigation 96(6): 2820-2827.
Clarke, J. F., P. W. Young, K. Yonezawa, M. Kasuga and G. D. Holman (1994). "Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin." Biochem J 300 ( Pt 3): 631- 635.
Cochet, C., J. J. Feige, F. Pirollet, M. Keramidas and E. M. Chambaz (1982). "Selective inhibition of a cyclic nucleotide independent protein kinase (G type casein kinase) by quercetin and related polyphenols." Biochem Pharmacol 31(7): 1357-1361.
Coelho Rabello Lima, L., C. Oliveira Assumpcao, J. Prestes and B. Sergio Denadai (2015). "CONSUMPTION OF CHERRIES AS A STRATEGY TO ATTENUATE EXERCISE-INDUCED MUSCLE DAMAGE AND INFLAMMATION IN HUMANS." Nutr Hosp 32(5): 1885-1893.
Collier, C. A., C. R. Bruce, A. C. Smith, G. Lopaschuk and D. J. Dyck (2006). "Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle." Am J Physiol Endocrinol Metab 291(1): E182-189.
Cook, M. D., S. D. Myers, M. L. Gault and M. E. T. Willems (2017). "Blackcurrant Alters Physiological Responses and Femoral Artery Diameter during Sustained Isometric Contraction." Nutrients 9(6).
Cooper, K. A., J. L. Donovan, A. L. Waterhouse and G. Williamson (2008). "Cocoa and health: a decade of research." Br J Nutr 99(1): 1-11.
Cosentino, F., K. Hishikawa, Z. S. Katusic and T. F. Luscher (1997). "High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells." Circulation 96(1): 25-28.
Costa, L. G., J. M. Garrick, P. J. Roquè and C. Pellacani (2016). "Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More." Oxidative Medicine and Cellular Longevity 2016: 2986796.
Costantini, S., G. Di Bernardo, M. Cammarota, G. Castello and G. Colonna (2013). "Gene expression signature of human HepG2 cell line." Gene 518(2): 335-345.
Crandall, J. P., V. Oram, G. Trandafirescu, M. Reid, P. Kishore, M. Hawkins, H. W.